Postpartum pelvic organ prolapse and pelvic floor muscle training: secondary analysis of a randomized controlled trial of primiparous women.

INTRODUCTION AND HYPOTHESIS: Pelvic floor dysfunction is common after childbirth. We hypothesize that physiotherapist-guided pelvic floor muscle training (PFMT) is effective regarding pelvic organ prolapse (POP) symptoms during the first postpartum year. METHODS: This was a secondary analysis from a randomized controlled trial (RCT), carried out at a physiotherapy clinic, Reykjavik. Participants were eighty-four primiparous women with a singleton delivery. They were screened for eligibility 6-13 weeks postpartum. Women in a training group conducted 12 weekly individual sessions with a physiotherapist within an RCT, starting on average 9 weeks postpartum. Outcomes were assessed after the last session (short term) and at approximately 12 months postpartum (long term). The control group received no instructions after the initial assessment. Main outcome measures were self-evaluated POP symptoms by the Australian Pelvic Floor Questionnaire. RESULTS: Forty-one and 43 women were in the training and control groups, respectively. At recruitment, 17 (42.5%) of the training group and 15 (37%) of the control group reported prolapse symptoms (p = 0.6). Five (13%) from the training group and nine (21%) controls were bothered by the symptoms (p = 0.3). There was a gradual decrease in the number of women with symptoms and no significant short-term (p = 0.08) or long-term (p = 0.6) differences between the groups regarding rates of women with POP symptoms. The difference between groups regarding bother in the short (p = 0.3) or longer term (p = 0.4) was not significant. Repeated-measures analyses using Proc Genmod in SAS did not indicate a significant effect of the intervention over time (p > 0.05). CONCLUSIONS: There was an overall decrease in postpartum symptoms of POP and bother during the first year. Physiotherapist-led PFMT did not change the outcomes. CLINICAL TRIAL REGISTRATION: The trial was registered 30 March 2015 at https://register. CLINICALTRIALS: gov (NCT02682212). Initial participant enrollment was on 16 March 2016 and reported following CONSORT guidelines for randomized controlled trials.

When does fetal head rotation occur in spontaneous labor at term: results of an ultrasound-based longitudinal study in nulliparous women.

BACKGROUND: Improved information about the evolution of fetal head rotation during labor is required. Ultrasound methods have the potential to provide reliable new knowledge about fetal head position. OBJECTIVE: The aim of the study was to describe fetal head rotation in women in spontaneous labor at term using ultrasound longitudinally throughout the active phase. STUDY DESIGN: This was a single center, prospective cohort study at Landspitali - The National University Hospital of Iceland, Reykjavík, Iceland, from January 2016 to April 2018. Nulliparous women with a single fetus in cephalic presentation and spontaneous labor onset at ≥37 weeks' gestation were eligible. Inclusion occurred when the active phase could be clinically established by labor ward staff. Cervical dilatation was clinically examined. Fetal head position and subsequent rotation were determined using both transabdominal and transperineal ultrasound. Occiput positions were marked on a clockface graph with 24 half-hour divisions and categorized into occiput anterior (≥10- and ≤2-o'clock positions), left occiput transverse (>2- and <4-o'clock positions), occiput posterior (≥4- and ≤8 o'clock positions), and right occiput transverse positions (>8- and <10-o'clock positions). Head descent was measured with ultrasound as head-perineum distance and angle of progression. Clinical vaginal and ultrasound examinations were performed by separate examiners not revealing the results to each other. RESULTS: We followed the fetal head rotation relative to the initial position in the pelvis in 99 women, of whom 75 delivered spontaneously, 16 with instrumental assistance, and 8 needed cesarean delivery. At inclusion, the cervix was dilated 4 cm in 26 women, 5 cm in 30 women, and ≥6 cm in 43 women. Furthermore, 4 women were examined once, 93 women twice, 60 women 3 times, 47 women 4 times, 20 women 5 times, 15 women 6 times, and 3 women 8 times. Occiput posterior was the most frequent position at the first examination (52 of 99), but of those classified as posterior, most were at 4- or 8-o'clock position. Occiput posterior positions persisted in >50% of cases throughout the first stage of labor but were anterior in 53 of 80 women (66%) examined by and after full dilatation. The occiput position was anterior in 75% of cases at a head-perineum distance of ≤30 mm and in 73% of cases at an angle of progression of ≥125° (corresponding to a clinical station of +1). All initial occiput anterior (19), 77% of occiput posterior (40 of 52), and 93% of occiput transverse positions (26 of 28) were thereafter delivered in an occiput anterior position. In 6 cases, the fetal head had rotated over the 6-o'clock position from an occiput posterior or transverse position, resulting in a rotation of >180°. In addition, 6 of the 8 women ending with cesarean delivery had the fetus in occiput posterior position throughout the active phase of labor. CONCLUSION: We investigated the rotation of the fetal head in the active phase of labor in nulliparous women in spontaneous labor at term, using ultrasound to provide accurate and objective results. The occiput posterior position was the most common fetal position throughout the active phase of the first stage of labor. Occiput anterior only became the most frequent position at full dilatation and after the head had descended below the midpelvic plane.

Fetal descent in nulliparous women assessed by ultrasound: a longitudinal study.

BACKGROUND: Ultrasound measurements offer objective and reproducible methods to measure the fetal head station. Before these methods can be applied to assess labor progression, the fetal head descent needs to be evaluated longitudinally in well-defined populations and compared with the existing data derived from clinical examinations. OBJECTIVE: This study aimed to use ultrasound measurements to describe the fetal head descent longitudinally as labor progressed through the active phase in nulliparous women with spontaneous onset of labor. STUDY DESIGN: This was a single center, prospective cohort study at the Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland, from January 2016 to April 2018. Nulliparous women with a single fetus in cephalic presentation and spontaneous labor onset at a gestational age of ≥37 weeks, were eligible. Participant inclusion occurred during admission for women with an established active phase of labor or at the start of the active phase for women admitted during the latent phase. The active phase was defined as an effaced cervix dilated to at least 4 cm in women with regular contractions. According to the clinical protocol, vaginal examinations were done at entry and subsequently throughout labor, paired each time with a transperineal ultrasound examination by a separate examiner, with both examiners being blinded to the other's results. The measurements used to assess the fetal head station were the head-perineum distance and angle of progression. Cervical dilatation was examined clinically. RESULTS: The study population comprised 99 women. The labor patterns for the head-perineum distance, angle of progression, and cervical dilatation differentiated the participants into 75 with spontaneous deliveries, 16 with instrumental vaginal deliveries, and 8 cesarean deliveries. At the inclusion stage, the cervix was dilated 4 cm in 26 of the women, 5 cm in 30 of the women, and ≥6 cm in 43 women. One cesarean and 1 ventouse delivery were performed for fetal distress, whereas the remaining cesarean deliveries were conducted because of a failure to progress. The total number of examinations conducted throughout the study was 345, with an average of 3.6 per woman. The ultrasound-measured fetal head station both at the first and last examination were associated with the delivery mode and remaining time of labor. In spontaneous deliveries, rapid head descent started around 4 hours before birth, the descent being more gradual in instrumental deliveries and absent in cesarean deliveries. A head-perineum distance of 30 mm and angle of progression of 125° separately predicted delivery within 3.0 hours (95% confidence interval, 2.5-3.8 hours and 2.4-3.7 hours, respectively) in women delivering vaginally. Although the head-perineum distance and angle of progression are independent methods, both methods gave similar mirror image patterns. The fetal head station at the first examination was highest for the fetuses in occiput posterior position, but the pattern of rapid descent was similar for all initial positions in spontaneously delivering women. Oxytocin augmentation was used in 41% of women; in these labors a slower descent was noted. Descent was only slightly slower in the 62% of women who received epidural analgesia. A nonlinear relationship was observed between the fetal head station and dilatation. CONCLUSION: We have established the ultrasound-measured descent patterns for nulliparous women in spontaneous labor. The patterns resemble previously published patterns based on clinical vaginal examinations. The ultrasound-measured fetal head station was associated with the delivery mode and remaining time of labor.

Cross-sectional study of early postpartum pelvic floor dysfunction and related bother in primiparous women 6-10 weeks postpartum.

INTRODUCTION AND HYPOTHESIS: To study the prevalence of pelvic floor dysfunction and related bother in primiparous women 6-10 weeks postpartum, comparing vaginal and cesarean delivery. METHODS: Cross-sectional study of 721 mothers with singleton births in Reykjavik, Iceland, 2015 to 2017, using an electronic questionnaire. Information on urinary and anal incontinence, pelvic organ prolapse and sexual dysfunction with related bother (trouble, nuisance, worry, annoyance) was collected. Main outcome measures were prevalence of pelvic floor dysfunction and related bother. RESULTS: The overall prevalence of urinary and anal incontinence was 48% and 60%, respectively. Bother regarding urinary symptoms was experienced by 27% and for anal symptoms by 56%. Pelvic organ prolapse was noted by 29%, with less than half finding this bothersome. Fifty-five percent were sexually active, of whom 66% reported coital pain. Of all the women, 48% considered sexual issues bothersome. Urinary incontinence and pelvic organ prolapse were more prevalent in women who delivered vaginally compared to cesarean section, but no differences were observed for anal incontinence and coital pain. Compared to women with BMI < 25, obesity was a predictor for urinary incontinence after vaginal delivery (OR 1.94; 95% CI 1.20-3.14). Birthweight > 50th percentile was predictive for urgency incontinence after vaginal delivery (OR 1.53; 95% CI 1.05-2.21). Episiotomy predicted more anal incontinence (OR 2.19; 95% CI 1.30-3.67). No associations between maternal and delivery characteristics were found for pelvic floor dysfunction after cesarean section. CONCLUSIONS: Bothersome pelvic floor dysfunction symptoms are prevalent among first-time mothers in the immediate postpartum period.

Can postpartum pelvic floor muscle training reduce urinary and anal incontinence?: An assessor-blinded randomized controlled trial.

BACKGROUND: Pelvic floor dysfunction, including urinary and anal incontinence, is a common postpartum complaint and likely to reduce quality of life. OBJECTIVE: To study the effects of individualized physical therapist-guided pelvic floor muscle training in the early postpartum period on urinary and anal incontinence and related bother, as well as pelvic floor muscle strength and endurance. MATERIALS AND METHODS: This was an assessor-blinded, parallel-group, randomized controlled trial evaluating effects of pelvic floor muscle training by a physical therapist on the rate of urinary and/or anal leakage (primary outcomes); related bother and muscle strength and endurance in the pelvic floor were secondary outcomes. Between 2016 and 2017, primiparous women giving birth at Landspitali University Hospital in Reykjavik, Iceland, were screened for eligibilty 6-10 weeks after childbirth. Of those identified as urinary incontinent, 95 were invited to participate, of whom 84 agreed. The intervention, starting at ∼9 weeks postpartum consisted of 12 weekly sessions with a physical therapist, after which the main outcomes were assessed (endpoint, ∼6 months postpartum). Additional follow-up was conducted at ∼12 months postpartum. The control group received no instructions after the initial assessment. The Fisher exact test was used to test differences in the proportion of women with urinary and anal incontinence between the intervention and control groups, and independent-sample t tests were used for mean differences in muscle strength and endurance. Significance levels were set as α = 0.05. RESULTS: A total of 41 and 43 women were randomized to the intervention and control groups, respectively. Three participants and 1 participant withdrew from these respective groups. Measurement variables and main delivery outcomes were not different at recruitment. At the endpoint, urinary incontinence was less frequent in the intervention group, with 21 participants (57%) still symptomatic, compared to 31 controls (82%) (P = .03), as was bladder-related bother with 10 participants (27%) in the intervention vs 23 (60%) in the control group (P = .005). Anal incontinence was not influenced by pelvic floor muscle training (P = .33), nor was bowel-related bother (P = .82). The mean differences between groups in measured pelvic floor muscle strength changes at endpoint was 5 hPa (95% confidence interval, 2-8; P = .003), and for pelvic floor muscle endurance changes, 50 hPa/s (95% confidence interval, 23-77; P = .001), both in favor of the intervention group. The mean between-group differences for anal sphincter strength changes was 10 hPa (95% confidence interval, 2-18; P = .01) and for anal sphincter endurance changes 95 hPa/s (95% confidence interval, 16-173; P = .02), both in favor of the intervention. At the follow-up visit 12 months postpartum, no differences were observed between the groups regarding rates of urinary and anal incontinence and related bother. Pelvic floor- and anal muscle strength and endurance favoring the intervention group were maintained. CONCLUSION: Postpartum pelvic floor mucle training decreased the rate of urinary incontinence and related bother 6 months postpartum and increased muscle strength and endurance.

Effects of an intervention program for reducing severe perineal trauma during the second stage of labor.

BACKGROUND: Obstetric anal sphincter injuries lead frequently to short- and long-term consequences for the mother, including perineal pain, genital prolapse, and sexual problems. The aim of the study was to evaluate whether the implementation of an intervention program in the second stage of labor involving altered perineal support techniques reduced severe perineal trauma. METHODS: All women reaching the second stage of labor and giving birth vaginally to singleton babies at Landspítali University Hospital (comprising 76% of births in Iceland in 2013) were enrolled in a cohort study. Data were recorded retrospectively for 2008-2010 and prospectively in 2012-2014, for a total of 16 336 births. During 2011, an intervention program was implemented, involving all midwives and obstetricians working in the labor wards. Two professionals assessed and agreed on classification of every perineal tear. RESULTS: The prevalence of obstetric anal sphincter injuries decreased from 5.9% to 3.7% after the implementation (P < 0.001). Third-degree tears decreased by 40%, and fourth-degree tears decreased by 56% (P < 0.001). The prevalence of first-degree tears increased from 25.8% to 33.1%, whereas second-degree tears decreased from 44.7% to 36.6% between the before and after study periods. Severe perineal trauma was linked to birthweight, and this did not change despite the new intervention. CONCLUSIONS: Active intervention to reduce perineal trauma was associated with an overall significant decrease in obstetric anal sphincter injuries. Good perineal visualization, manual perineal support, and controlled delivery of the fetal head were essential components for reducing perineal trauma.

Maternal deaths in the Nordic countries.

INTRODUCTION: Despite the seriousness of the event, maternal deaths are substantially underreported. There is often a missed opportunity to learn from such tragedies. The aim of the study was to identify maternal deaths in the five Nordic countries, to classify causes of death based on internationally acknowledged criteria, and to identify areas that would benefit from further teaching, training or research to possibly reduce the number of maternal deaths. MATERIAL AND METHODS: We present data for the years 2005-2013. National audit groups collected data by linkage of registers and direct reporting from hospitals. Each case was then assessed to determine the cause of death, and level of care provided. Potential improvements to care were evaluated. RESULTS: We registered 168 maternal deaths, 90 direct and 78 indirect cases. The maternal mortality ratio was 7.2/100 000 live births ranging from 6.8 to 8.1 between the countries. Cardiac disease (n = 29) was the most frequent cause of death, followed by preeclampsia (n = 24), thromboembolism (n = 20) and suicide (n = 20). Improvements to care which could potentially have made a difference to the outcome were identified in one-third of the deaths, i.e. in as many as 60% of preeclamptic, 45% of thromboembolic, and 32% of the deaths from cardiac disease. CONCLUSION: Direct deaths exceeded indirect maternal deaths in the Nordic countries. To reduce maternal deaths, increased efforts to better implement existing clinical guidelines seem warranted, particularly for preeclampsia, thromboembolism and cardiac disease. More knowledge is also needed about what contributes to suicidal maternal deaths.

Maternal deaths in Iceland over 25 years.

INTRODUCTION: Maternal death, during pregnancy or within 42 and 365 days from the end of pregnancy, was evaluated for a small high-income nation with comprehensive healthcare. MATERIAL AND METHODS: Cases were identified using record linkage by running national census information on all deaths of women aged 15-49 years during 1985-2009 against the national birth register and computerized hospital admission files for pregnancy-related diagnoses as well as actual case records where needed. Death certificates and hospital records were reviewed. RESULTS: Thirty deaths were identified; 26 at ≥ 22 weeks (= birth) and four earlier in pregnancy. For 107,871 deliveries, the overall mortality was 27.8/100,000. There were five direct deaths (4.6/100,000 deliveries), five indirect deaths (4.6/100,000 deliveries) and 19 coincidental deaths (17.6/100,000 deliveries). Using WHO criteria (direct and indirect in pregnancy or at ≤ 42 days postpartum) the ratio was 5.6/100,000 deliveries (95% confidence interval 1.1-10.1) and 5.5/100,000 live births (maternal mortality ratio, based on six deaths). Direct deaths were caused by sepsis, severe preeclampsia and choriocarcinoma, indirect by suicide, pre-existing cardiac and diabetic illness. No woman died of postpartum hemorrhage, anesthesia or ectopic pregnancy. Suboptimal care occurred. CONCLUSION: Maternal mortality in Iceland over a 25-year period up to the end of year 2010 was low, between 5 and 6/100,000 births. A comprehensive national healthcare system with accessible antenatal care in a society with good general living conditions and universal education probably contributed to this.

Physical activity of relatively high intensity in mid-pregnancy predicts lower glucose tolerance levels.

INTRODUCTION: Physical activity (PA) is recommended as part of therapy for patients with impaired glucose tolerance. Whether such recommendations are also justified for pregnant women is less well established. We investigated the association between PA and glucose tolerance in pregnancy. MATERIAL AND METHODS: A non-selective sample of 217 pregnant women was recruited at a routine 20 week ultrasound examination. Participants answered the International Physical Activity Questionnaire (IPAQ) about frequency, intensity and duration of daily physical activity in the past 7 days and underwent oral glucose tolerance testing (OGTT) between 24 and 28 weeks. A subset of 72 overweight/obese pregnant women wore a pedometer for 1 week with assessment of IPAQ score and pedometric correlations to this. RESULTS: Of the sample, 177 attended for OGTT; 51% were overweight or obese. The mean (SD) fasting glucose was 4.5 (0.4) mmol/L, and 12% had gestational diabetes mellitus. Only one-third engaged in vigorous PA. After adjustment for pre-pregnancy BMI, age and parity, those engaging in vigorous PA had significantly lower fasting glucose levels (by 0.15 mmol/L, 95% CI 0.03-0.27) compared with those not vigorously active. This decrease was similar in both normal and overweight/obese women. There were fewer cases of gestational diabetes (p = 0.03) among the vigorously active women (3/56; 5%) than among those who were not active (19/121; 16%). No association with glucose tolerance was observed for physical activity of moderate intensity. CONCLUSIONS: Only vigorous physical activity appears beneficial with respect to maternal glucose tolerance, both among normal, overweight and obese women.

Mode of delivery and subsequent reproductive patterns. A national follow-up study.

OBJECTIVE: To investigate associations between mode of delivery and subsequent reproductive outcomes. DESIGN: Cohort study. POPULATION: Women with term singleton live births from 1987 to 2009. SETTING: Denmark, birth registration data. METHODS: Women with a first singleton delivery after 37 weeks were followed until the end of 2010, from a first birth to include subsequent live births. We used Cox's proportional hazards model stratified by parity to compare the likelihood for subsequent delivery according to mode of delivery at first and later births, estimating maternal age effects and lag time to next delivery. MAIN OUTCOME MEASURE: Likelihood of a subsequent live-born child by previous delivery mode. RESULTS: We identified 642,052 women with a first delivery. Compared with women with a non-instrumental vaginal delivery, delivering a child by elective cesarean section implied a 23% (95% CI 0.76-0.787) decreased likelihood for subsequent delivery. Emergency cesarean section meant 16% fewer (95% CI 0.84-0.85), and vaginal instrumental delivery 4% fewer subsequent deliveries (95% CI 0.95-0.96). Hazard ratios were largely unchanged after controlling for parity and year of birth. Small age-trends were seen, with hazard ratios affected by maternal age at birth. Delivery mode at first birth affected marginally the time lag until next birth. CONCLUSIONS: Fecundity, measured as likelihood of a successive live-born child, varied with mode of delivery at the first and also subsequent births. A first or later delivery by cesarean section implied decreased likelihood of subsequent delivery compared with women with a first vaginal birth.

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Can ultrasound on admission in active labor predict labor duration and a spontaneous delivery?

BACKGROUND: Identifying predictive factors for a normal outcome at admission in the labor ward would be of value for planning labor care, timing interventions, and preventing labor dystocia. Clinical assessments of fetal head station and position at the start of labor have some predictive value, but the value of ultrasound methods for this purpose has not been investigated. Studies using transperineal ultrasound before labor onset show possibilities of using these methods to predict outcomes. OBJECTIVE: This study aimed to investigate whether ultrasound measurements during the first examination in the active phase of labor were associated with the duration of labor phases and the need for operative delivery. STUDY DESIGN: This was a secondary analysis of a prospective cohort study at Landspitali University Hospital, Reykjavík, Iceland. Nulliparous women at ≥37 weeks' gestation with a single fetus in cephalic presentation and in active spontaneous labor were eligible for the study. The recruitment period was from January 2016 to April 2018. Women were examined by a midwife on admission and included in the study if they were in active labor, which was defined as regular contractions with a fully effaced cervix, dilatation of ≥4 cm. An ultrasound examination was performed by a separate examiner within 15 minutes; both examiners were blinded to the other's results. Transabdominal and transperineal ultrasound examinations were used to assess fetal head position, cervical dilatation, and fetal head station, expressed as head-perineum distance and angle of progression. Duration of labor was estimated as the hazard ratio for spontaneous delivery using Kaplan-Meier curves and Cox regression analysis. The hazard ratios were adjusted for maternal age and body mass index. The associations between study parameters and mode of delivery were evaluated using receiver operating characteristic curves. RESULTS: Median times to spontaneous delivery were 490 minutes for a head-perineum distance of ≤45 mm and 682 minutes for a head-perineum distance of >45 mm (log-rank test, P=.009; adjusted hazard ratio for a shorter head-perineum distance, 1.47 [95% confidence interval, 0.83-2.60]). The median durations were 506 minutes for an angle of progression of ≥93° and 732 minutes for an angle of progression of <93° (log-rank test, P=.008; adjusted hazard ratio, 2.07 [95% confidence interval, 1.15-3.72]). The median times to delivery were 506 minutes for nonocciput posterior positions and 677 minutes for occiput posterior positions (log-rank test, P=.07; adjusted hazard ratio, 1.52 [95% confidence interval, 0.96-2.38]) Median times to delivery were 429 minutes for a dilatation of ≥6 cm and 704 minutes for a dilatation of 4 to 5 cm (log-rank test, P=.002; adjusted hazard ratio, 3.11 [95% confidence interval, 1.68-5.77]). Overall, there were 75 spontaneous deliveries; among those deliveries, 16 were instrumental vaginal deliveries (1 forceps delivery and 15 ventouse deliveries), and 8 were cesarean deliveries. Head-perineum distance and angle of progression were associated with a spontaneous delivery with area under the receiver operating characteristic curves of 0.68 (95% confidence interval, 0.55-0.80) and 0.67 (95% confidence interval, 0.55-0.80), respectively. Ultrasound measurement of cervical dilatation or position at inclusion was not significantly associated with spontaneous delivery. CONCLUSION: Ultrasound examinations showed that fetal head station and cervical dilatation were associated with the duration of labor; however, measurements of fetal head station were the variables best associated with operative deliveries.

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

No correlation between cesarean section rates and perinatal mortality of singleton infants over 2,500 g.

A rising cesarean section rate has been suggested as of benefit in reducing the already low perinatal death rates seen in developed countries for infants of normal birthweight. Iceland has one of the lowest national corrected and uncorrected perinatal mortality rates. Information was collected through the Icelandic birth registry for all 82,251 deliveries of non-malformed singletons weighing > or = 2,500 g at birth, for the 20 years 1987-2006. The mean birthweight-specific perinatal mortality rate for these pregnancies was 2.0/1,000 per year (range 0.8-4.1/1000) without significant changes over the study period. The cesarean section rate varied between 11.9 and 16.7% and did not correlate with the perinatal mortality rate. Among the nulliparous women, cesarean section rates increased from 13.1 to 17.9% without correlation to the perinatal mortality, which on average was 1.7/1,000. A further benefit from rising cesarean section rates at term in countries with a prior low perinatal mortality is questioned.

Quantification of menstrual flow by weighing protective pads in women with normal, decreased or increased menstruation.

OBJECTIVE: To investigate the association between menstrual flow weight measured from modern sanitary pads (converting liquid to non-evaporating gel) and clinically assessed normal, increased or decreased menstrual flow. DESIGN: Objective method development study. SETTING: Outpatient clinic, University Hospital, Reykjavik. POPULATION: One hundred and thirteen volunteers included 26 normally menstruating adult women and 52 normally menstruating teenagers not using oral or intrauterine contraception, seven normally menstruating women using oral contraception, 17 women with clinically diagnosed menorrhagia, five women using oral contraception for clinical menorrhagia, and six teenage girls claiming heavy menstrual flow. METHODS: Menstruation length, menstrual flow weight and history of iron deficiency were assessed. During the menstruation following recruitment, all women collected their used protective pads in a hygienic manner and returned them to the laboratory for accurate weighing. MAIN OUTCOME MEASURES: Menstrual flow total weight measured in grams. RESULTS: Mean menstrual flow total weight in the 78 asymptomatic women was 51 g (median 44, range 5-144). The mean flow in 17 women clinically diagnosed with menorrhagia was 217 g (median 207, range 63-402) (p<0.0001 compared to healthy women). The seven healthy women using oral contraceptives discharged 13 g (13-19) (p=0.0004 compared with normals). Menstruation lasted < eight days in 77/78 healthy women and in 12 of 17 clinically diagnosed menorrhagic women. CONCLUSIONS: Measurement of menstrual flow total weight accurately reflects clinically assessed normal, increased and decreased flow. The method is an easy and accurate way of objectively estimating menstrual flow.

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.

Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth.

Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism.

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10-8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

Recurrence of hypertensive disorder in second pregnancy.

OBJECTIVE: The purpose of this study was to investigate the recurrence of hypertensive disorders in pregnancy with regard to the type of disorder, the onset of hypertension, and the modulating effect of overweight and weight gain between pregnancies. STUDY DESIGN: Maternity records from 896 parous women with hypertensive disorders in pregnancy in the first pregnancy were reviewed to reclassify disease status and calculate odds ratios for recurrence. RESULTS: Recurrence of hypertensive disorders in pregnancy occurred in 58% to 94% of second pregnancies, depending on first pregnancy disorder. Overweight (odds ratio, 1.82) and weight gain (odds ratio, 2.20) were related to recurrence among women with gestational hypertension. Early hypertension (